Constitutional mutations of the CHEK2 gene are a risk factor for MDS, but not for de novo AML

2018 ◽  
Vol 70 ◽  
pp. 74-78 ◽  
Author(s):  
Hanna Janiszewska ◽  
Aneta Bąk ◽  
Katarzyna Skonieczka ◽  
Anna Jaśkowiec ◽  
Marek Kiełbiński ◽  
...  
Keyword(s):  
Risk Factor ◽  
De Novo ◽  
Chek2 Gene ◽  
De Novo Aml

BAALC expression predicts clinical outcome of de novo acute myeloid leukemia patients with normal cytogenetics: a Cancer and Leukemia Group B Study

Blood ◽  
2003 ◽  
Vol 102 (5) ◽  
pp. 1613-1618 ◽  
Author(s):  
Claudia D. Baldus ◽  
Stephan M. Tanner ◽  
Amy S. Ruppert ◽  
Susan P. Whitman ◽  
Kellie J. Archer ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Factor ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Free Survival ◽  
De Novo Aml ◽  
Normal Cytogenetics ◽  
Group B ◽  
Leukemia Group ◽  
Acute Myeloid

AbstractCytogenetic aberrations are important prognostic factors in acute myeloid leukemia (AML). Of adults with de novo AML, 45% lack cytogenetic abnormalities, and identification of predictive molecular markers might improve therapy. We studied the prognostic impact of BAALC (Brain And Acute Leukemia, Cytoplasmic), a novel gene involved in leukemia, in 86 de novo AML patients with normal cytogenetics who were uniformly treated on Cancer and Leukemia Group B 9621. BAALC expression was determined by comparative real-time reverse transcriptase–polymerase chain reaction in pretreatment blood samples, and patients were dichotomized at BAALC's median expression into low and high expressers. Low expressers had higher white counts (P = .03) and more frequent French-American-British M5 morphology (P = .007). Compared to low expressers, high BAALC expressers showed significantly inferior overall survival (OS; median, 1.7 vs 5.8 years, P = .02), event-free survival (EFS; median, 0.8 vs 4.9 years, P = .03), and disease-free survival (DFS; median, 1.4 vs 7.3 years, P = .03). Multivariable analysis confirmed high BAALC expression as an independent risk factor. For high BAALC expressers the hazard ratio of an event for OS, EFS, and DFS was respectively 2.7, 2.6, and 2.2. We conclude that high BAALC expression predicts an adverse prognosis and may define an important risk factor in AML with normal cytogenetics.

Impact of Post-Remission Treatments in Patients Aged 65–70 Years with De Novo AML: A Comparison of Two Concomitant Randomized ALFA Trials with Overlapping Age Inclusion Criteria

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 557-557
Author(s):  
Raphael Itzykson ◽  
Claude Gardin ◽  
Cécile Pautas ◽  
Xavier Thomas ◽  
Pascal Turlure ◽  
...  
Keyword(s):  
Risk Factor ◽  
De Novo ◽  
Univariate Analysis ◽  
Significant Risk ◽  
High Dose ◽  
Inclusion Criteria ◽  
Aged Patients ◽  
Ambulatory Treatment ◽  
De Novo Aml ◽  
The Impact

Abstract Background: The outcome of older patients with AML treated with intensive chemotherapy remains poor. No standard of treatment for post-remission therapy been demonstrated in these patients, and repeated high-dose cytarabine (AraC) post-remission courses have only been shown of benefit in patients aged of 50 years or less. Objective: To compare the overall outcome and the impact of post-remission strategies in patients with newly-diagnosed AML aged 65 to 70 years and enrolled during the same period (12/1999 to 10/2006) in two concomitant randomized ALFA trials with overlapping age inclusion criteria. The ALFA-9803 study (Gardin et al, Blood, 2007) was designed for elderly patients (65y+ with de novo or post-MDS AML) while the ALFA-9801 trial was designed for middle-aged patients (50–70y with de novo AML) (Pautas et al. ASH 2007 #162). All other inclusion criteria were similar among the two trials. Patients and Treatments: Analysis was restricted to the 211 patients aged 65–70y with de novo AML. A frontline randomization between idarubicin (IDA) and daunorubicin (DNR) was included in the two trials, with a total IDA/DNR dose of 36/180 mg and 36–48/240 mg during induction, for the 9803 and 9801 trial respectively. After induction, both trials essentially differed by the post-remission chemotherapy, which comprised two intermediate-dose cytarabine (IDAC) cycles in the 9801 trial and a second randomization between one repeated 3+7 like cycle and six 1+5 anthracycline-based ambulatory consolidations in the 9803 trial. Only two patients received a stem cell transplantation in first CR (1 allogeneic, 1 autologous). In both studies, the initial randomization between IDA and DNR had no impact on OS. Nevertheless, all analyses were stratified on IDA/DNR randomization arm. Results: Seventy-six patients were treated in the 9801 trial and 135 in the 9803 trial. Median age was 67 years and M/F sex ratio was 110/101. Median WBC was 7.4 G/L. Cytogenetic risk was favorable in 9 (4%), intermediate in 118 (56%) and unfavorable in 54 (26%) patients, respectively. Ninety-five and 116 patients were randomized to receive DNR and IDA, respectively. Aside from median age (67 vs 68 years in 9801 and 9803, respectively; P<.001), patient characteristics were similar between the two protocol subgroups, in terms of inclusion date, sex, PS, FAB, cytogenetics, and WBC. The overall CR rate was 62%. In univariate analysis, there was a trend for a higher CR rate in the younger 9801 trial (70 vs 57%; p=.17). As expected, cytogenetics was identified as the sole significant risk factor for CR achievement (89% in favorable, 68% in intermediate, and 44% in unfavorable-risk; p=0.03). Median follow-up, OS, RFS, and EFS were 35, 14, 12 and 6.5 months, respectively. In univariate analysis, the trial did not influence OS (3-year OS, 20 vs 17% in the 9801 and 9803 trial, respectively; p=.71), RFS or EFS. Again, the only identified risk factor for OS and EFS was high-risk cytogenetics. After CR achievement, 44 9801-patients (58%) received the planned IDAC consolidation, while 30 (22%) and 33 (24%) 9803-patients received the planned 3+7 like or ambulatory consolidation, respectively. In these patients, no significant differences in CR duration (median CR duration: 12.4, 14.8 and 11.9 months with IDAC, 3+7 like, and ambulatory consolidation, respectively; p=0.57) was observed among these three different post-remission strategies. In multivariate analysis, only unfavorable cytogenetics affected OS (HR=1.8 [95% CI 1.3–2.6], p=10-3) and EFS (HR=2.0 [1.4–2.8], p<10-4), with a trend for adverse RFS (HR=1.6 [.99–2.7], p=.055). Conclusion: In patients aged 65–70 years with de novo AML, more intensive post-remission therapy containing IDAC does not appear to significantly improve EFS, RFS, or OS, as compared to less intensive consolidation or even repeated anthracyclin-based ambulatory treatment. The poor early outcome of those with unfavorable cytogenetics justifies the evaluation of new global therapeutic approaches in this patient subset.

scholarly journals Rapid expansion of preexisting nonleukemic hematopoietic clones frequently follows induction therapy for de novo AML

Blood ◽  
2016 ◽  
Vol 127 (7) ◽  
pp. 893-897 ◽  
Author(s):  
Terrence N. Wong ◽  
Christopher A. Miller ◽  
Jeffery M. Klco ◽  
Allegra Petti ◽  
Ryan Demeter ◽  
...  
Keyword(s):  
Induction Therapy ◽  
De Novo ◽  
Rapid Expansion ◽  
Key Points ◽  
De Novo Aml

Key Points Hematopoietic populations unrelated to the AML founding clone often expand after induction therapy, resulting in oligoclonal hematopoiesis.

Antileukemic activity of rapamycin in acute myeloid leukemia

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2527-2534 ◽  
Author(s):  
Christian Récher ◽  
Odile Beyne-Rauzy ◽  
Cécile Demur ◽  
Gaëtan Chicanne ◽  
Cédric Dos Santos ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Mammalian Target Of Rapamycin ◽  
Cell Types ◽  
Mtor Inhibition ◽  
Growth And Survival ◽  
Clinical Responses ◽  
De Novo Aml ◽  
Acute Myeloid

AbstractThe mammalian target of rapamycin (mTOR) is a key regulator of growth and survival in many cell types. Its constitutive activation has been involved in the pathogenesis of various cancers. In this study, we show that mTOR inhibition by rapamycin strongly inhibits the growth of the most immature acute myeloid leukemia (AML) cell lines through blockade in G0/G1 phase of the cell cycle. Accordingly, 2 downstream effectors of mTOR, 4E-BP1 and p70S6K, are phosphorylated in a rapamycin-sensitive manner in a series of 23 AML cases. Interestingly, the mTOR inhibitor markedly impairs the clonogenic properties of fresh AML cells while sparing normal hematopoietic progenitors. Moreover, rapamycin induces significant clinical responses in 4 of 9 patients with either refractory/relapsed de novo AML or secondary AML. Overall, our data strongly suggest that mTOR is aberrantly regulated in most AML cells and that rapamycin and analogs, by targeting the clonogenic compartment of the leukemic clone, may be used as new compounds in AML therapy.

scholarly journals The Prognostic Impact of the Diagnostic CD34+/CD38- Cell Burden and Expression of the Stem Cell Marker GPR56 after Stem Cell Transplantation Depends on the AML Origin

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 323-323
Author(s):  
Madlen Jentzsch ◽  
Marius Bill ◽  
Juliane Grimm ◽  
Dominic Brauer ◽  
Julia Schulz ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Solid Tumors ◽  
Cell Transplantation ◽  
Research Funding ◽  
De Novo ◽  
Prognostic Impact ◽  
Expression Levels ◽  
Rheumatologic Diseases ◽  
De Novo Aml

Introduction: Acute myeloid leukemia (AML) developing secondary after other hematologic diseases, or therapy related after cytotoxic treatment for solid tumors or rheumatologic diseases (s/tAML) is clinically, genetically & prognostically distinct from de novo diseases. Data indicate that s/tAML patients (pts) have inferior outcome compared to de novo cases after chemotherapy & therefore often require consolidation therapy using allogeneic stem cell transplantation (HSCT). Leukemic stem cells (LSC) initiate & maintain AML. They are also believed to exist within the CD34+/CD38- &/or high GPR56 expressing bone marrow (BM) population, which have been shown to impact adversely on outcome. The prognostic impact of LSC markers in de novovs s/tAML after HSCT with non-myeloablative conditioning intensity - where the therapeutic approach also relies on immunological graft-versus-leukemia effects - is unknown. Methods: We analyzed 379 AML pts who received an allogeneic peripheral blood HSCT in complete remission (CR, 82%) or CR with incomplete peripheral recovery (CRi, 18%) between 1999 & 2018 after non-myeloablative (3x30 mg/m2 Fludarabine & 2 Gy total body irradiation) conditioning. At diagnosis, cytogenetic & flow cytometric analyses were performed centrally. For pts with pre-treatment BM available the mutation status of CEBPA, NPM1 & presence of FLT3-ITD by fragment analyses as well as expression levels of GPR56 by qPCR were assessed. Using a next-generation targeted amplicon sequencing approach we analyzed a panel comprising 54 recurrently mutated (mut) genes in myeloid malignancies on the MiSeq platform (Illumina). Median follow up after HSCT was 3.7 years. Results: 229 pts (60%) had de novo & 150 pts (40%) had AML secondary to myelodysplastic syndrome (MDS, n=82), myeloproliferative neoplasm (MPN, n=22) or MDS/MPN (n=10), or therapy related after Non-Hodgkin lymphoma (n=9), solid tumors (n=25) or rheumatologic diseases (n=2). At diagnosis, s/tAML pts had lower white blood counts (P=.03), lower blasts in BM (P<.001) or blood (P=.007) & a higher BM CD34+/CD38- cell burden (P=.01) & GPR56 expression (P=.04). They also had worse European LeukemiaNet risk (P=.007), were less likely to have a normal karyotype by trend (P=.06), to have a core binding factor AML (P=.02), to be NPM1mut (P=.003), DNMT3Amut (P=.03) & to harbor a FLT3-ITD (P=.002) but more likely to be JAK2mut (P<.001). Comparing pts with s/tAML vsde novo AML, there was no significant different cumulative incidence of relapse (CIR, P=.85) or overall survival (OS, P=.29). Next, we evaluated the prognostic impact of the LSC-associated populations in pts with de novo or s/tAML separately. In pts with de novo AML, we observed a significantly higher CIR & shorter OS for pts harboring a high CD34+/CD38- cell burden (high vs low, 6% cut, P=.006 [Fig. 1A] & P=.003) & a higher CIR but not significantly different OS for pts with a low GPR56 expression (high vs low, median cut, P=.03 [Fig. 1B] & P=.95). Combining both parameters, we observed a stepwise higher CIR & shorter OS for pts with low expression of both variables vs pts with a low CD34+/CD38- cell burden but high GPR56 expression vs pts with a high CD34+/CD38-cell burden (P=.003 [Fig. 1C] & P=.05). In contrast, in pts with s/tAML, there was no prognostic significance of the CD34+/CD38- cell burden (CIR P=.38 [Fig. 1D] & OS P=.95), the GPR56 expression (CIR P=.64 [Fig. 1E] & OS P=.82) & both markers combined (CIR P=.57 [Fig. 1F] & OS P=.98). Also in multivariate analyses, the combination of both markers significantly impacted CIR (Hazard ratio 2.49, P<.001 after adjustment for donor type) & was the only significant factor for OS (Odds Ratio 0.68, P=.04) in de novo AML but not in s/tAML. Conclusion: While there was no significantly different CIR or OS in s/tAML compared to de novo AML pts undergoing non-myeloablative HSCT we observed a significant impact on outcome for the known LSC-associated prognosticators CD34+/CD38- cell burden & GPR56 expression levels at diagnosis only in de novo AML pts. Different underlying disease biology & possibly different LSC-associated populations may be relevant for disease reoccurrence in s/tAML. Figure Disclosures Jentzsch: Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria. Niederwieser:Daichii: Speakers Bureau; Cellectis: Consultancy. Platzbecker:Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Schwind:Daiichi Sankyo: Honoraria; Novartis: Honoraria, Research Funding.

A patient with de novo AML M1 and t(16;21) with karyotype evolution

2007 ◽  
Vol 31 (9) ◽  
pp. 1319-1321 ◽  
Author(s):  
Andrea Zatkova ◽  
Christa Fonatsch ◽  
Wolfgang R. Sperr ◽  
Peter Valent
Keyword(s):  
Karyotype Evolution ◽  
De Novo ◽  
De Novo Aml

Efficacy and safety of aspacytarabine (BST-236) as a single-agent, first-line therapy for patients with acute myeloid leukemia unfit for standard chemotherapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7007-7007
Author(s):  
Jessica K. Altman ◽  
Jamie Koprivnikar ◽  
James K. McCloskey ◽  
Vamsi Kota ◽  
Olga Frankfurt ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
De Novo ◽  
Single Agent ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
First Line ◽  
Standard Chemotherapy ◽  
First Line Therapy ◽  
Line Therapy ◽  
De Novo Aml

7007 Background: Aspacytarabine (BST-236) is a prodrug of cytarabine, the backbone of acute myeloid leukemia (AML) standard of care chemotherapy, associated with toxicity which precludes its administration in older patients and patients with comorbidities. Aspacytarabine is inactive in its intact prodrug form until cytarabine is gradually released at pharmacokinetics which decrease the systemic exposure to peak toxic cytarabine levels, resulting in reduced systemic toxicity and relative sparing of normal tissues, enabling therapy with high cytarabine doses to patients otherwise unfit to receive it. Methods: A phase 2b open-label, single-arm study to evaluate the efficacy and safety of aspacytarabine as a first-line single-agent therapy in newly-diagnosed AML patients unfit for standard chemotherapy (NCT03435848). Aspacytarabine is administrated at 4.5 g/m2/d (containing 3 g/m2/d cytarabine) in 1-2 induction and 1-3 consolidation courses, each consisting of 6 daily 1-hour infusions. Patients with secondary AML, prior hypomethylating agent (HMA) therapy, and therapy-related AML, are eligible. Results: To date, in the ongoing study, 46 newly-diagnosed AML patients unfit for standard chemotherapy (median age 75 years) were treated with aspacytarabine and completed 1-4 courses of 4.5 g/m2/d aspacytarabine, including 26 patients (63%) with de novo AML and 17 (37%) with secondary AML. Six patients (13%) were previously treated with HMA (median 12 courses). The baseline median bone marrow blasts was 52%, and 54% and 29% of patients had adverse or intermediate European LeukemiaNet (ELN) score, respectively. Twenty (43%) patients had ECOG 2. Aspacytarabine is safe and well-tolerated in repeated-course administration. Grade > 2 drug-related adverse events include mainly hematological events and infections. The 30-day mortality rate is 11%. Of 43 patients evaluable for efficacy analysis to date, 15 patients (35%) reached a complete remission (CR) following 1 (13 patients) or 2 (2 patients) induction courses, all with complete hematological recovery (median 27.5 days, range 22-39 days). The CR rates in de novo AML patients and patients with adverse ELN score are 46% and 33%, respectively. Of the 11 patients evaluable to date for minimal residual disease (MRD) flow cytometry test, 8 are MRD negative (73%). While aspacytarabine treatment consists of a limited number of courses, median duration of response and median overall survival for responders are not reached at 12 and 24 months, respectively (end of follow up). Updated results will be presented at the meeting. Conclusions: The cumulative clinical data suggest that aspacytarabine, a time-limited single-agent treatment, is safe and efficacious as a first-line therapy for patients who are unfit for intensive chemotherapy, which may establish it as a new tolerable AML chemotherapy backbone. Clinical trial information: NCT03435848.

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